Subjective cognitive complaints in older adults have previously been linked to cross-sectional brain differences within the left mesial temporal region including medial temporal lobe atrophy (Rooden et al., 2018), reduced hippocampal volume (Saykin et al., 2006), and decreased parahippocampal white matter diffusivity (Wang et al., 2012). While some investigators have reported a link between white matter hyperintensities (WMH) in the brain and subjective cognitive complaints (Dey et al., 2019; Morrison et al., 2023), the role of region-specific risk is unclear.  The goal of this study was to learn whether region-specific WMH load is associated with subjective cognitive complaints. We hypothesized that greater temporal WMH load would be associated with more memory complaints in older adults with a family history of Alzheimer’s disease (AD).

Participants included 154 older adults with subjective cognitive complaints and a first-degree family history of AD [characteristics: mean age=71.21 years, SD=5.04; mean education=16.25 years, SD=2.36; 63% women; 88% white non-Hispanic]. Screening and baseline data were drawn from an ongoing NIA-funded multi-site Phase 2 clinical trial of a photobiomodulation intervention. Subjective cognitive complaints were operationalized using the Cognitive Change Index-20 (CCI-20) involving self-rated changes in various cognitive activities relative to 5 years ago (1=no change, 5=much worse); items were summed into a total score and memory, executive function, and language subdomains. WMH volumes were derived from a fully automated extraction pipeline (i.e., Unidentified Bright Objects (UBO) Detector) using MP-RAGE 3D T1-weighted and high-resolution 3D FLAIR sequences from Siemens 3T scanners. WMHs were split into sample-based tertiles (i.e., low, medium, and high volumes). Separate bootstrapped analyses of covariance (controlling for age, site, and intracranial volume) compared CCI-20 total and subdomain scores across the three severity levels of WMH total and regional volumes (i.e., deep, periventricular, and left/right frontal, temporal, parietal, occipital); pairwise comparisons used Bonferroni corrections.

Subjective memory complaints were significantly different across WMH severity levels only in the left temporal lobe (F=4.07, p=0.02, partial η²=0.05); individuals with high WMH load had significantly more subjective memory complaints than those with low WHM load (CCI-20 memory subdomain mean=25.66 vs. 22.32, respectively; p=0.01, 95% CI=0.59-5.75), with a trending difference for medium load (mean=23.16; p=0.07, 95% CI=-0.27-5.20). The low and medium WMH load groups did not differ (p=0.47). No other significant differences were present.

We found that greater white matter burden in the left temporal lobe, but not other regions, was associated with more memory complaints. This finding aligns with past work linking subjective complaints to a variety of temporal-region specific changes and expands evidence to include a cerebrovascular marker, a common comorbidity with AD. Like past research (Dhana et al., 2022), this finding suggests a potential threshold effect: only after reaching higher WMH loads in the left temporal lobe does a relationship with subjective memory complaints emerge. While WMH’s relationship to subjective complaints has been studied in older adults, to our knowledge, this is the first study to examine this link in older adults with a family history of AD. Future work should examine WMH’s utility for predicting future subjective complaints in this population.